Treg Conditioning Endows Activated Teff with Suppressor Function in Autoimmune Hepatitis/Autoimmune Sclerosing Cholangitis

Abstract

Imbalance between T regulatory (Treg) and T effector (Teff) cells is likely to contribute to induction and perpetuation of liver damage in autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC) either through inability of Tregs to restrain proliferation and effector cytokine production by responders or through conversion of Tregs into T helper type 1 (Th1) or type 17 (Th17) effector lymphocytes.

We investigated the effect of Treg skewing on the phenotypic and functional properties of CD4⁺CD127⁺CD25^high cells, an activated subset of Teff, in 32 patients with AIH, 20 with AISC and in 36 healthy subjects (HS).

In AIH/AISC we note a substantial increase in peripheral blood derived CD4⁺CD127⁺CD25^high cells that display a Th1/Th17 phenotypic profile, as reflected by heightened IFNγ and IL-17 production, as well as by high levels of T-bet and RORC expression, and which is strongly correlated with disease activity. CD4⁺CD127⁺CD25^high cells are unresponsive to low dose IL-2 and in patients have marked proliferative ability, further enhanced by stimulation with IL-7. CD4⁺CD127⁺CD25^high cells obtained from CD4⁺ cells exposed to Treg polarizing conditions display enhanced IL-10 production, upregulate CD49b and LAG-3, markers of T regulatory 1 (Tr1) cells, and effectively suppress responder cell proliferation both in health and AIH/AISC patients through a mechanism which is dependent on IFNγ and IL-17. Suppressive function of CD4⁺CD127⁺CD25^high cells is maintained upon pro-inflammatory challenge in HS but not in AIH/AISC.

Conclusion: Treg skewing confers activated Teff phenotypic and functional properties of Tr1 cells in health and in AIH/AISC, though suppressive function is lost in patients upon pro-inflammatory challenge. Protracted modulation of the inflammatory environment is required to attenuate the effector potential while boosting immunoregulatory properties in Teff. This article is protected by copyright. All rights reserved.

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